肝细胞色素P450 3A4代谢活性对氯吡格雷抵抗现象的作用。

Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance.

作者信息

Lau Wei C, Gurbel Paul A, Watkins Paul B, Neer Charlene J, Hopp Amy S, Carville David G M, Guyer Kirk E, Tait Alan R, Bates Eric R

机构信息

Department of Anesthesiology, University of Michigan Health System, 1G323 University Hospital, Box 0048, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0048, USA.

出版信息

Circulation. 2004 Jan 20;109(2):166-71. doi: 10.1161/01.CIR.0000112378.09325.F9. Epub 2004 Jan 5.

DOI:10.1161/01.CIR.0000112378.09325.F9

PMID:14707025

Abstract

BACKGROUND

Interindividual variability of platelet inhibition after aspirin or clopidogrel administration has been described. Additionally, aspirin resistance and clopidogrel resistance occur in some individuals. Because the prodrug clopidogrel is activated by hepatic cytochrome P450 (CYP) 3A4, we hypothesized that interindividual variability in clopidogrel efficacy might be related to interindividual differences in CYP3A4 metabolic activity.

METHODS AND RESULTS

Platelet aggregation was measured before and after clopidogrel treatment in 32 patients undergoing coronary artery stent implantation and in 35 healthy volunteers. The erythromycin breath test was used to measure CYP3A4 activity in vivo in 25 of the healthy volunteers. Individual platelet aggregation was studied in 10 healthy volunteers after the coadministration of clopidogrel and rifampin (a CYP3A4 inducer). Clopidogrel nonresponders, low responders, and responders were defined by a relative inhibition of adenosine diphosphate (20 micromol/L)-induced platelet aggregation of <10%, 10% to 29%, and > or =30%, respectively. Among patients, 22% were clopidogrel nonresponders, 32% were low responders, and 47% were responders. Among volunteers, 16% were nonresponders, 12% were low responders, and 72% were responders. Percent platelet aggregation after clopidogrel inversely correlated with CYP3A4 activity (r=-0.6, P=0.003). Improved platelet inhibition in volunteers resistant to clopidogrel was observed with the coadministration of clopidogrel and rifampin.

CONCLUSIONS

Clopidogrel administration results in interindividual variability in platelet inhibition, which correlates with CYP3A4 metabolic activity. Measurement of antiplatelet drug efficacy with a point-of-care device and alternative antithrombotic strategies for aspirin or clopidogrel nonresponders and low responders could reduce the incidence of thrombotic events that continue to occur despite oral antiplatelet therapy.

摘要

背景

已有研究报道了阿司匹林或氯吡格雷给药后血小板抑制的个体间变异性。此外，一些个体还存在阿司匹林抵抗和氯吡格雷抵抗现象。由于前体药物氯吡格雷是由肝细胞色素P450（CYP）3A4激活，我们推测氯吡格雷疗效的个体间变异性可能与CYP3A4代谢活性的个体差异有关。

方法与结果

对32例行冠状动脉支架植入术的患者和35名健康志愿者在氯吡格雷治疗前后测量血小板聚集情况。对25名健康志愿者采用红霉素呼气试验来测量体内CYP3A4活性。在10名健康志愿者中联合给予氯吡格雷和利福平（一种CYP3A4诱导剂）后研究个体血小板聚集情况。根据二磷酸腺苷（20 μmol/L）诱导的血小板聚集相对抑制率分别<10%、10%至29%和≥30%来定义氯吡格雷无反应者、低反应者和反应者。在患者中，22%为氯吡格雷无反应者，32%为低反应者，47%为反应者。在志愿者中，16%为无反应者，12%为低反应者，72%为反应者。氯吡格雷治疗后的血小板聚集百分比与CYP3A4活性呈负相关（r = -0.6，P = 0.003）。联合给予氯吡格雷和利福平后，观察到对氯吡格雷耐药的志愿者血小板抑制情况有所改善。